Triple-drug therapy with ivermectin, diethylcarbamazine and albendazole for the acceleration of lymphatic filariasis elimination in Kenya: Programmatic implementation and results of the first impact assessment

The World Health Organization (WHO) endorsed the use of triple-drug mass drug administration (MDA) regimen with ivermectin, diethylcarbamazine (DEC) and albendazole (commonly abbreviated as IDA) to accelerate the elimination of lymphatic filariasis (LF) as a public health problem in settings where onchocerciasis is not co-endemic. The National Programme for Elimination of LF (NPELF) in Kenya was among the first adopters of the IDA-MDA and two annual rounds were provided in 2018 and 2019 to the residents of Lamu County and Jomvu sub-County in the coast region. This study documented the feasibility of successfully delivering the two rounds of IDA-MDA. An operational research study was undertaken to determine efficient sampling strategies, indicators, and the appropriate population groups that could be used for the monitoring and evaluation of LF programs using IDA-MDA for the elimination of the disease as a public health problem. Two cross-sectional surveys were conducted at baseline in 2018 before IDA-MDA and an impact assessment 17 months after the second round of IDA-MDA. The reported epidemiological treatment coverage was at least 80% in all implementation units during each round of IDA-MDA. Blood samples were tested for filarial antigenemia using commercial Filariasis Test Strips (FTS) and any individual found to be positive was tested again at night for the presence of microfilariae in finger prick blood smears using microscopy. The overall prevalence of circulating filarial antigen (CFA) was relatively low at the baseline survey with Jomvu having 1.39% (95% CI: 0.91, 2.11) and Lamu having 0.48% (95% CI: 0.21, 1.13). Significant reduction in CFA prevalence was observed during the impact assessment after the two annual rounds of mass treatment. The overall relative reduction (%) in CFA prevalence following the two rounds of MDA with IDA was significant in both Jomvu (52.45%, Z = -2.46, P < 0.02) and Lamu (52.71%, Z = -1.97, P < 0.05). Heterogeneity, however, was observed in the CFA prevalence reduction between random and purposive clusters, as well as between adult and child populations. The results of the impact assessment survey offered strong evidence that it was safe to stop the IDA-MDA in the two EUs because transmission appears to have been interrupted. It is also important to implement a post-treatment surveillance system which would enable efficient detection of any recrudescence of LF transmission at a sub-evaluation unit level. Our findings show that IDA-MDA may be considered for acceleration of LF elimination in other settings where onchocerciasis is not co-endemic.


Introduction
Lymphatic filariasis (LF), commonly known as elephantiasis, is a mosquito-borne neglected tropical disease (NTD) caused by infection with the filarial nematode species Wuchereria bancrofti, Brugia malayi or B. timori [1].The parasites are transmitted from person to person by mosquitoes belonging to the genera Culex, Anopheles, Mansonia and Aedes.Clinically, LF infection may be asymptomatic, but can also lead to acute and chronic conditions, including lymphoedema (swelling of the tissues, primarily the legs) and hydrocele (scrotal swelling).In 2000, the World Health Organization (WHO) launched the Global Programme to Eliminate LF (GPELF) as a public health problem [2,3].The GPELF has two principal aims: (i) to interrupt LF transmission, and (ii) to manage morbidity and prevent disability.To interrupt transmission of LF, the GPELF recommends annual community-wide mass drug administration (MDA) of two-drug treatment regimen (albendazole plus either ivermectin or diethylcarbamazine) to entire at-risk populations for 4 to 6 years at adequate levels of coverage.Modelling studies have estimated adequate treatment coverage to be at least 65% of the total population in endemic areas [4,5].
It is estimated that the GPELF resulted in substantial health and economic benefits during the period 2000-2014 [6].Overall, an estimated 36 million clinical cases and 175 million disability-adjusted life years (DALYs) were potentially averted during the period.In economic terms, an estimated US$100.5 billion was potentially saved through medical expenses, potential income loss, and costs to the health system.
Approximately 4 million people residing in six counties (23 sub-counties) of the coastal region of Kenya, including Kilifi, Kwale, Lamu, Tana River, Mombasa, and Taita Taveta are considered to be at-risk of LF infection.Kenya started an MDA programme with diethylcarbamazine (DEC) plus albendazole in 2002 in the then Kilifi district and expanded to include Malindi and Kwale districts in 2003.The geographic coverage was progressively expanded over the years to include other districts in the coastal region except Mombasa city and its periurban areas.However, the programme faced financial and operational challenges which led to MDA being missed in some years and complete cessation after the 2011 MDA.Nonetheless, the non-consecutive rounds of MDA led to considerable reduction in the prevalence of LF [7].The MDA programme was restarted in 2015 and baseline population surveys confirmed that CFA prevalence was still greater than the 2% antigenemia threshold in several areas [8], thus justifying the resumption of MDA campaigns.
Findings of clinical trials conducted in Papua New Guinea have shown that co-administration of the three drugs used to treat LF (ivermectin, DEC, and albendazole-IDA) results in improved efficacy for clearing W. bancrofti microfilariae (Mf), which is the stage of the filarial parasite that is ingested by mosquitoes, and sterilization of adult filarial worms [9,10].In 2017, following a thorough review process of data from safety and efficacy trials of the triple-drug regimen, the WHO recommended it as an alternative MDA regimen for the acceleration of LF elimination [11].The guidelines recommend the use of annual IDA in specific settings where onchocerciasis is not co-endemic with LF including places where MDA has not yet started, fewer than 4 effective MDA rounds have been administered, and where MDA results have been sub-optimal.Following the WHO's formal approval and release of the alternative treatment guidelines, Merck and the MECTIZAN Donation Program (MDP) promised to work with the WHO, national LF programs and other stakeholders to develop a mechanism to enable for the deployment of any required additional donation [12].The announcement was a major enabler for the adoption of the IDA regimen by endemic countries.Computer simulation modelling suggests that the triple-drug regimen has the potential to dramatically accelerate the elimination of LF if epidemiological treatment coverage is high and systematic noncompliance is low [13].
Sentinel site surveys conducted throughout the coastal region in 2015 and 2016 identified Lamu East and Jomvu sub-counties as the sites with the highest prevalence of LF (6.3% and 6.7% antigenemia, respectively) [8].Lamu county had received one round of MDA in 2011 and additional two rounds in 2016 and 2017 using the two-drug regimen of DEC and albendazole, and all the three MDA rounds had achieved effective coverage (i.e., �65% of the total population was treated).Jomvu, however, had received two rounds of MDA (in 2016 and 2017), but none exceeded the 65% treatment coverage threshold.Due to the relatively high prevalence of LF, the intermittent history of MDA and the sub-optimal coverage, both Lamu county and Jomvu sub-county were selected to receive two annual rounds of IDA in order to accelerate LF elimination.
In evaluation units where two-drug MDA is given for 5 to 6 consecutive years and the LF infection reduced to the recommended thresholds, the WHO recommends post-MDA surveillance using transmission assessment surveys (TAS) among six-and seven-year-old children [14].Critical cut-off values of numbers of circulating filarial antigen (CFA) positive children are employed to determine whether transmission has been interrupted in the evaluation units.While the TAS has proven to be an effective tool for basing MDA stopping decisions under the standard two-drug regimens, it is unclear whether the target age group and epidemiologic target (<2% antigenemia in areas with W. bancrofti infections) are appropriate when IDA is used.A follow-on study to the clinical trial in Papua New Guinea found that a single dose of IDA sterilizes adult filarial worms for at least 5 years, but may fail to clear CFA (15).The study suggests that a better biomarker or a different surveillance strategy will be needed to assess the effect of the three-drug regimen on LF populations.In this paper, we report on the NPELF experience delivering MDA with IDA in three implementation units in coastal Kenya.Because IDA was anticipated to result in an accelerated interruption of transmission, an operational research study was nested within the work of the national program with the goal of establishing the target population(s), infection indicator(s), sampling strategies, and thresholds required to determine when it is safe to stop MDA with IDA.Consequently, in this paper we present both the experience of the NPELF in delivering IDA as well as the baseline and impact assessment survey results from the closely related operational research study in two evaluation units following IDA implementation.

Ethics statement
Ethical approval of the study protocols and informed consent documents was obtained from the Scientific and Ethics Review Unit of the Kenya Medical Research Institute (KEMRI/SERU Protocol No. 3721 and 4099).The study was conducted following the tenets of the Helsinki Declaration.An information sheet was provided and read to all eligible participants during study enrollment.Written informed consent was obtained from adults and parents or legal guardians of children less than18 years old included in the study.Additionally, written assent was obtained from children aged 13 years to <18 years.No study participants' identifiers were included in the dataset used for the analyses in order to ensure privacy.

Study sites
Two rounds of MDA with IDA were provided in November 2018 and November 2019 in three sub-counties on the Kenyan coast: two (Lamu East and Lamu West sub-counties) in Lamu County and the other one (Jomvu sub-County) in Mombasa County.For the IDA impact assessment, Lamu County, which is comprised of a mainland and several islands and is situated on north coast of Kenya near the border with Somalia, was considered as a single Evaluation Unit (EU), due to its relatively low population.Jomvu sub-county formed the second EU and encompasses a mixture of urban, peri-urban and a few rural areas.In both EUs, the village served as the primary sampling unit (PSU) for the cluster sampling survey.

Approach for MDA implementation
Due to the critical importance of achieving high treatment coverage for MDA with IDA, and the fact that the new triple-drug regimen required ingestion of more medicines than the twodrug regimen (DEC and albendazole) used previously, various strategies were implemented to bolster compliance and treatment coverage.

Robust partnerships.
Local and international collaborations played a pivotal role in supporting the program's execution.Partners such as Evidence Action, The Task Force for Global Health's NTD Support Center, and the END Fund provided essential logistical, technical, and financial support, thus contributing to the successful implementation of the program.Evidence Action with support from the END Fund provided fiscal management and technical assistance in the following areas: design and procurement of training materials including those for advocacy, communication, and social mobilization (ACSM); logistics for drug delivery; and budget management for county and sub-county training and sensitization.The Kenya Medical Research Institute (KEMRI) with support from the NTD Support Center at The Task Force for Global Health provided technical support for baseline and impact assessment surveys, as well as monitoring and evaluation (M&E).The African Institute for Health and Development (AIHD) conducted formative research that influenced the review of ACSM materials and identified specific population segments with lower program engagement that may benefit from intensified mobilization.The description and results of the formative research will be reported elsewhere.
Adverse event management and pharmacovigilance tools.Since clinical trials in Papua New Guinea had shown that IDA-MDA is superior in parasite clearance, it was anticipated that there would be a heightened risk of adverse events (AEs) which necessitated deployment of a robust pharmacovigilance framework.Collaboration with Kenya's Pharmacy and Poisons Board (PPB) enabled the implementation of comprehensive pharmacovigilance tools, including reporting forms.Medications to help manage any AEs were procured and stocked, including cetirizine, paracetamol, and prednisolone.The AE forms were part of the training manuals and community drug distributors' (CDD) handbooks.To ensure that any community members' questions or concerns about the drugs could be promptly addressed, the PPB gave their hotline numbers to be used in case of the occurrence of serious adverse events (SAEs).
Enhanced community engagement and supervision.Community health extension workers (CHEWs) played a pivotal role in engaging communities through community meetings (commonly known as baraza) and supportive supervision of the CDDs.The number of individuals targeted by each CDD was reduced from 500 to 300, which allowed the CDD to spend more time in each household to answer any questions, ensure accurate dosing and recording, and to directly observe the medicines being swallowed.There was also closer supervision of CDDs, with one CHEW overseeing ten CDDs, compared to 20 in the conventional two-drug MDA.Additionally, the duration of the IDA-MDA campaigns lasted for six days, compared to five days in the conventional two-drug MDA.All of these adjustments allowed the implementers to pay closer attention to detail including assuring the community members of the safety and importance of taking the medicines.Frequent echo-messaging was done with the CHEWs and chiefs reminding them of the key LF and IDA-MDA information they needed to share with their constituents through intense social mobilization.
Innovative delivery strategies to reach program targets.Special attention was given to areas that were historically challenging to access, thus addressing the needs of populations that may have been missed during the two-drug MDA campaigns.To maximize treatment coverage, the program ventured beyond conventional strategies by directly administering MDA in industrial areas and utilizing boats to reach remote islands.Fixed posts, temporary fixed posts, and door-to-door distribution were among the treatment strategies employed.For the first time, MDA was taken directly to factories in the industrial areas.This was an innovative way to capture populations typically missed by MDA campaigns by meeting them where they usually spend their days.Boats were also hired to reach the far-off islands that were previously missed and branded as hard-to-reach areas.
Effective CDD selection and health care workers training.The selection of CDDs was a crucial determinant of program success.By recruiting retired health professionals and individuals from private chemists, the program leveraged the community's trust in these respected persons.Similar strategies were employed in gated communities to enhance acceptance among diverse populations.These individuals are well known to the community members as health professionals which encouraged uptake.In the gated communities, prior appointments had to be made and members of these communities were selected as CDDs to boost the trust of these 'upper class' individuals.Training of CHEWs and other sub-county implementation teams was centralized and conducted simultaneously for all the cadres in order to ensure that accurate information was provided, and to minimize loss of information about the new triple-drug therapy down the cascade.
Involvement of champions.The involvement of individuals directly affected by the disease as LF champions during the MDA campaigns added a human element to the program.The narratives of the LF champions were shared during program launches, encouraging community members to actively participate in the IDA-MDA.During the launch of the campaign in Lamu, for example, these individuals openly explained how their lives had been negatively affected by LF, and dispelled the commonly held belief that hydrocele surgery would particularly make the men infertile.The support of the top leadership in the implementation areas was also critical for ensuring the success of the campaigns.In Lamu, for example, the Governor graced the IDA-MDA campaign launch and openly swallowed the medicines (a total of 9 pills) which sent a strong message that the intervention is indeed safe.

Survey design and sampling strategy
Cross-sectional epidemiological and entomological baseline surveys and IDA impact assessment were conducted in 30 and 5-10 random and purposive clusters (villages), respectively.This report, however, focuses on the population-based epidemiological survey arm for which the baseline survey was conducted in October-November, 2018 and the impact assessment in April-May, 2021.The village served as the primary sampling unit (PSU) in this study.A two-armed sampling strategy was employed to select random and purposive PSUs as described below.
Random sampling.All PSUs in the EU were listed in geographical order along with their respective population sizes from which 30 PSUs (aka 'clusters') were selected using probability proportionate to estimated size (PPES) sampling.An Excel tool was created to aid study investigators in the selection of the clusters.
Purposive sampling.During the baseline survey, 5 clusters in each EU were selected to become the purposive PSUs, based on suspicion of high transmission of LF.The selection of the 5 purposive clusters was done in consultation with the NPELF officers and local health workers.During the impact assessment, however, up to 10 clusters were purposively selected.To maximize the chances of selecting sites with ongoing transmission during the impact assessment, the purposive clusters were chosen to be the 5 villages with the highest CFA prevalence in children 5-9 years of age in the baseline survey and up to 5 additional villages that had the greatest proportion of positive mosquito pools (if these sites were different from the initial 5 selected villages based on CFA prevalence in children).If there were fewer than 5 sites with CFA positive children, the CFA prevalence in adults was used to determine greatest risk of LF transmission for the purposive site selection.

Human sample size
Since the mosquito vectors responsible for LF transmission in coastal Kenya belong to Culex and Anopheles species [16], the sample size was powered to enable the detection of a 2% CFA threshold for each of two age groups: [1] children aged 5-9 years old and other community members aged >10 years during the baseline survey, and [2] children aged 5-9 years-old and other community members aged �18 years during the impact assessment.The upper age group was changed to �18 years for the impact assessment because it became clear that the 10-17 years age group would be challenging for NTD programs to assess and interpret if it were to become global guidance, due to varying rates of boarding school attendance and the age at which children enter the work sector.The sample size of the 5-9 years-old children that was required for the random cluster survey in each area was selected to be similar to the sample sizes used for the WHO-recommended TAS survey [14].The target population and sample size were adjusted for the impact survey based on WHO's interim guidance to use a 1% Mf threshold in adults (�18 years) with 95% confidence to assess the impact of IDA [17].S1 and S2 Tables show the sample sizes that were required during each survey time point.In each survey, the individuals were enrolled to participate if they had lived in the areas for at least 12 months.

Blood sampling and testing for LF infection
Blood sampling was done in two human populations: children (age 5-9 years) and older persons (age �10 and �18 years in baseline and impact assessment surveys, respectively).The blood specimens were tested for CFA in the field using the Filariasis Test Strip (FTS) as recommended by the manufacturer (Alere, Scarborough, Maine, USA).Briefly, 75μl of finger prick blood was collected from each consenting participant into one of the plastic capillary tubes provided by the manufacturer and placed on the test pad.The test results were read and recorded at 10 minutes.Additional blood specimen was collected from the same prick site for preparation of a dried-blood spot (DBS) specimen to be used for serological assays later.Any individuals found to be positive by the FTS test were followed up for a second blood specimen collection during hours of peak Mf circulation (9 pm-midnight).Approximately 60μl of the nighttime blood sample was used for thick blood smear microscopy and another 60μl for DBS preparation.The nighttime DBS samples were preserved for later detection of parasite DNA using a quantitative real-time polymerase chain reaction (qPCR) method.

Data management and analysis
In the field, data were collected on smartphones and regularly uploaded to an electronic database using the open-source software Secure Data Kit (SDK).Data sets were stored on a SQL secure server.Field staff were trained on how to use the tools for data collection in the field.The investigators had access to view and download the data sets in real time using a secure password-protected website.
A primary goal of the data analysis was to determine whether the decrease in CFA prevalence among children aged 5-9 years is consistent with TAS guidelines for stopping MDA, as compared to any decrease in CFA and Mf prevalence among adults.To address this primary study objective, the prevalence of CFA was assessed within each evaluation unit by each age group (5-9 years and �18 years) and the upper 1-sided 95% confidence limits calculated, assuming a hypergeometric distribution and taking into account survey design.
Infection prevalence was calculated and the 95% confidence intervals (CIs) determined using a binomial regression model, taking into account clustering by villages.To assess impact of IDA, the relative reductions (RR) in CFA prevalence at the impact assessment relative to baseline were calculated using multivariable mixed effects models with random intercepts for the clusters and implementation units and P-values obtained using Wald test.The relative reduction was calculated using the following formula.

Results
In Kenya, the MDA implementation unit is the sub-county (equivalent of district in most other African countries).Although Lamu County was considered as a single EU for the operational research study, the two sub-counties in this area were considered separate implementation units (IUs) during IDA-MDA.Table 1 shows the epidemiological treatment coverage (reported coverage) in the three IUs in 2018 and 2019.An independent treatment coverage evaluation survey undertaken soon after the IDA-MDA to validate the epidemiological treatment confirmed that high treatment coverage was indeed achieved (Table 1).
Overall, a total of 6,559 individuals were enrolled for the baseline survey out of whom 3,095 and 3,464 were from Lamu and Jomvu, respectively (Table 2).Out of 10,694 individuals enrolled during the IDA-MDA impact assessment survey, 5,235 and 5,459 were from Lamu and Jomvu, respectively.
Table 3 summarizes the prevalence of CFA in the two EUs, while comparing children and adult populations and the random and purposive clusters.In general, the overall CFA prevalence in both types of clusters was relatively low at the baseline survey, with Jomvu having 1.39% (95%CI: 0.91,2.11)and Lamu having 0.48% (95%CI: 0.21, 1.13).Of 15 CFA positive individuals identified during the baseline survey in Lamu, 3 were children between the ages of 5 and 9 years.In contrast, of the 48 CFA positive cases identified during the baseline survey in Jomvu, 11 were children aged 5-9 years.Of the 63 CFA positive cases during the baseline survey, one individual (a 45 years old male in Jomvu) was found to have three (3) Mf in his night blood sample.All the CFA positive individuals in the impact assessment survey provided a blood sample for Mf testing but none was found to have microfilaremia.
While there was an apparent reduction in the overall CFA prevalence following the administration of two rounds of MDA with IDA, the reduction was not consistent across the two EUs and study populations.Despite Lamu having very low numbers of CFA positive cases in the baseline survey, there was observed statistically significant decrease in prevalence between the baseline and impact assessment surveys, RR = 52.71%(Wald test: Z = -1.97,p = 0.049).This significant decline in Lamu was largely attributed to the random clusters, RR = 80.29% (Wald test: Z = -2.56,p = 0.011).In Jomvu, where CFA prevalence was relatively higher at baseline survey, the overall reduction in CFA prevalence was significant in the purposive villages, RR = 90.06%(Wald test: Z = -3.64,p < 0.001), but not in the random sites, RR = 39.70% (Wald test: Z = -1.97,p = 0.116).The reduction in CFA prevalence among the adult population after the two rounds of IDA-MDA in Jomvu was significant in both random, RR = 50.80%(Wald test: Z = -2.36,p = 0.018) and purposive, RR = 83.89%(Wald test: Z = -2.56,p = 0.010) clusters.Restricting the analysis to children in Jomvu, the reduction was only significant among the purposive villages, RR = 100.00%(Wald test: Z = -7.29,p < 0.001), but not in the randomly selected villages, RR = 52.70%(Wald test: Z = -0.91,p = 0.365).The 3 CFA positive children detected during the impact assessment survey in 2021 came from 3 different random villages in Jomvu.Two of these villages had overall CFA prevalence above 2% (2.68% and 3.60%) whereas the prevalence in other one village was below 2% (0.67%).In general, there was a greater number of CFA positive clusters in Jomvu compared with Lamu during both surveys (Table 4, and Figs 1 and 2).A total of 11 out of 35 clusters in Jomvu had CFA prevalence of 2% or above during the baseline survey, compared with 4 out of 39 clusters during the impact assessment survey.In contrast, Lamu had 2 out of 35 clusters with CFA prevalence of 2% or above during the baseline survey and 1 out of 36 clusters during the impact assessment survey.
At the impact assessment survey, none of the 5-9-year-old children tested for CFA were positive in Lamu, while 3 were found to be positive in Jomvu.Compared with the WHO recommended transmission assessment survey (TAS), the CFA positive child cases observed in both EUs were below the threshold (Table 5).

Discussion
Compliance to the triple-drug regimen MDA in Lamu county and Jomvu sub-county was high due to excellent social mobilization by the National Programme for Elimination of LF (NPELF) and implementing partners.The various integrated strategies that were employed during MDA with IDA in the two areas in coastal region of Kenya showcased how a comprehensive approach can be employed to achieve high treatment coverage.Through partnerships, tailored communication, robust adverse event management, community engagement, innovative delivery mechanisms, effective CDD selection, and the involvement of LF champions, the  program demonstrated the potential for achieving high treatment coverage.The treatment data demonstrated that the 80% treatment coverage target recommended by WHO could be realized.Indeed, the NPELF and partners were so successful in their social mobilization efforts that people from neighbouring sub-counties not meriting IDA-MDA travelled to Jomvu to receive the drugs (as is evident from the MDA coverage exceeding 100% in Jomvu).The results imply that NTD endemic communities will support the introduction of innovative treatments when the benefits of this change are clearly explained to them.
The results of the IDA-MDA impact assessment survey offered strong evidence that it was safe to stop the IDA regimen in the two EUs because transmission appears to have been interrupted.As a result of this survey, the Kenyan program stopped IDA-MDA in the two evaluation units and has since moved on to a period of surveillance.This study generated valuable data on the population, infection indicators, and sampling strategy that are effective for determining when it is safe to stop IDA-MDA.Adults had the greatest prevalence of CFA compared to children, suggesting that adults may be a preferred age group for IDA-MDA stopping decisions because they constitute a high-risk group for persistent infection.Despite the elevated CFA prevalence in the adult population, there was a significant reduction after the two rounds of annual IDA-MDA in the random clusters in both EUs.This reduction in CFA prevalence may be due to the low intensity of infections at baseline, and it would be interesting to determine if these results could be replicated in higher microfilarial intensity settings.A larger and more consistent reduction in CFA was seen in children across both the purposive and random sites in both EUs.
Importantly, measuring CFA alone may not be an adequate way for monitoring and evaluation of LF elimination programs using IDA-MDA [18].When IDA-MDA is used to accelerate the timeline to elimination (as opposed to the standard two-drug regimen which is delivered for 5+ years), there is not a clear interpretation for CFA results alone.Although the presence of filarial antigenemia in untreated individuals may be considered indicative of active W. bancrofti infection, its epidemiological significance in LF populations that have been given the required rounds of mass treatment is not clear.Indeed, evidence from initial IDA safety and efficacy clinical studies showed persistence of CFA for five years after a single dose treatment with IDA even with sustained clearance of Mf, which suggests sterilization of adult filarial worms albeit failure to clear filarial antigenemia [9,15].Consequently, it is important that a more definitive indicator, such as the presence of Mf, be used to confirm whether CFA positive individuals are contributing to ongoing transmission.Because patent infection can take up to years to develop from the time of exposure, testing of adults for microfilaremia might be more useful for public health monitoring.A CFA-positive, Mf-negative child may indicate the presence of immature worms that will later produce Mf.Unfortunately, very low microfilaremia prevalence at baseline (one positive individual) and apparent absence of Mf during the impact assessment does not allow for any direct conclusions regarding the suitability of microfilaremia as an indicator in the present study.The development of new and more sensitive diagnostics tools, particularly for use during post-MDA with IDA surveillance, is urgently required to detect recrudescence.The use of entomological sampling and molecular detection of filarial DNA in mosquito vectors, known as molecular xenomonitoring is also considered a surveillance tool for LF that may have particular utility in low prevalence settings, and thus could supplement the standard diagnostics [19][20][21].However, although molecular xenomonitoring can also be used to detect the presence of the parasite in mosquito vectors and is a sensitive indicator of microfilaraemia, it is not a direct measure of infectivity or current rates of parasite transmission [14].Another challenge with molecular xenomonitoring is that it is not yet known how to interpret a signal of infection in mosquitoes (e.g., what is the threshold for action?) and the approach is laborious, expensive and requires diagnostic equipment and techniques that aren't readily available to many NTD programs.
Interestingly, the comparison of randomly vs. purposively sampled sites leads to different conclusions in the two EUs.In Jomvu, the randomly sampled sites had a greater prevalence of CFA among adults compared to the purposively sampled sites at impact assessment (1.10% vs. 0.22%).Conversely, in Lamu the randomly sampled sites had a lower prevalence than the purposively sampled sites during the impact assessment (0.10% vs. 1.84%).While some of this difference may simply be random variation due to such low overall positive counts, it may also be driven by the differences between the two EUs.Jomvu is peri-urban with a lot of human movement, making it harder for the national program to know which sites were the highest risk areas for purposive selection.Lamu, in contrast, is less densely populated and has fewer known high-risk areas.It is important for future WHO guidance to recognize these two potential scenarios and develop a sampling strategy that balances purposive sampling with random; both strategies should be part of an overall MDA stopping decision to maximize the chance that areas with ongoing transmission are detected.
Prior to this study, the default recommendation for LF programs to determine whether IDA-MDA can be stopped is to follow the TAS methodology [11].In Kenya, due to the low The age group for the impact assessment survey was children 5-9 years compared to the 6-7 years recommended for TAS, which increased the risk for failing TAS. https://doi.org/10.1371/journal.pntd.0011942.t005 baseline prevalence and successful IDA implementation, the conclusion that it is safe to stop treatment would have been drawn from either the TAS in children or the impact assessment in adults.Nonetheless, the stark difference in prevalence between children and adults in both evaluation units highlights the risk of basing an IDA stopping decision on children.Furthermore, even in settings where the pre-IDA prevalence of antigenemia is greater than was observed in Kenya, the prevalence of antigenemia in children may remain above the target threshold after only two rounds of IDA, due to the persistence of an antigen signal; whereas measuring microfilaremia in adults is more likely to provide an accurate assessment of the potential for ongoing transmission in the population.
There is growing appreciation that basing MDA stopping decisions on the mean EU prevalence is not enough.As LF transmission approaches interruption, the remaining infection becomes increasingly focal and it is important to critically examine cluster-level results when determining whether a stop treatment decision is appropriate.The cluster data presented in Figs 1 and 2, as well as Table 4, present reassurance that post-IDA-MDA, there do not appear to be any remaining foci of infection that merit programmatic action.Nonetheless, the fact that four clusters in Jomvu and one in Lamu had a cluster-level FTS prevalence above 2% is an indication that the NPELF should remain vigilant of these sites during post-treatment surveillance to ensure that the lingering signal is a sign of waning infection and not recrudescence.Based on these findings, we suggest that future IDA impact survey guidance include consideration of not only the mean EU prevalence, but also provide guidance as to when cluster-level results merit targeted action.
In an effort to make impact assessments and post-treatment surveillance of NTDs costeffective in low-resource settings, the use of model-based geostatistics (MBG) has been proposed.MBG leverages spatial correlation within the data and enables one to design a survey that requires sampling fewer clusters and a smaller total sample size while achieving the same predictive qualities as conventional impact assessment [22,23].A reduction in sample size through MBG would be particularly beneficial in the context of IDA impact assessments because sampling of adults and collecting night blood is particularly onerous for survey teams.It is therefore important to consider a follow-on operational research study as part of the second IDA-MDA impact surveillance in the two EUs in order to provide additional evidence on the application of MBG-designed surveys.
This study has several limitations worth highlighting.The coast region of Kenya may be considered a low prevalence setting due to the impact of several rounds of the two-drug regimen MDA with DEC and albendazole and the widespread bednet usage.Lamu had received one round of MDA in 2011 (66% epidemiological treatment coverage) before the NPELF stopped mass treatments.Thereafter, Lamu received 3 rounds of consecutive MDA rounds in 2015, 2016 and 2017 and all were above the 65% epidemiological treatment threshold.Lamu was included primarily due to the historical persistence of LF infection in Lamu East particularly in Ndau island.With regard to Jomvu, two rounds of MDA with DEC and albendazole had been given in 2016 and 2017 but both were below the recommended 65% threshold.The low CFA prevalence and single Mf-positive adult at baseline made it challenging to detect any spatial or temporal patterns in prevalence between the two study time points.The missed opportunity to assess the impact of IDA-MDA on other diseases, particularly soil-transmitted helminthiasis (STH), scabies, and head lice may be considered a study limitation.Ivermectin is known to act strongly against a wide variety of insects, nematodes, and acarine parasites, including lice and scabies [24,25].A study to assess the impact of IDA-MDA for LF and STH control in Timor-Leste reported significant reduction in the prevalence of scabies, impetigo, and STH (Trichuris trichiura and Ascaris lumbricoides) among schoolchildren [26].
In this study, local and international partners provided significant financial and human resources which bolstered the national LF elimination program's efforts to deliver IDA-MDA with high treatment coverage.Considering that the health systems in low-and middle-income countries (LMICs) are often faced by limited resources and capacity, the need for the significant investment might be considered a limitation.A systematic review of factors that facilitate the implementation of high-quality MDA for LF in sub-Saharan Africa identified partnerships and collaborations as essential for sustained and successful implementation of MDA for LF [27].Thus, endemic countries that wish to accelerate the elimination of LF as a public health problem through IDA-MDA would need to establish strategic local and international partnerships, among other programmatic requirements.
A noteworthy strength of the study, however, is that the design of the cross-sectional surveys provided for the inclusion of both children and adult populations in both the baseline and impact assessment.The random sampling in Jomvu at baseline revealed pockets of ongoing transmission hitherto unknown to the NPELF.The results of the study also indicate that purposive sites have a critical role in LF surveillance, particularly in identifying areas with highest risk of LF transmission (putative hot spots).In Lamu for example, Ndau island is historically known to be an area with relatively high LF transmission [28], which was also confirmed during a previous survey [8].Laboratory serologic and molecular (PCR) results are still forthcoming and when reported will shine even greater light on the impact of MDA with IDA-both spatially and across the age groups.
In conclusion, this study shows that the two rounds of IDA-MDA reduced filarial antigenemia below the recommended thresholds in the two EUs.There are other sub-Saharan Africa countries that are endemic for LF but nonendemic for onchocerciasis or loiasis (e.g., Zanzibar, Comoros, Sao Tome and Principe, Eritrea, Madagascar, Zambia, and Zimbabwe), where IDA could be considered for the acceleration of their LF elimination programs [29].The study also demonstrated that programmatic delivery of MDA with IDA is a feasible and efficient strategy for endemic countries looking to accelerate their LF elimination programs as they move towards post-treatment surveillance.The operational research study highlights the utility of sampling adults in the context of IDA-MDA and shed important insight on the complementary role that random and purposive sampling can play in detecting pockets of ongoing transmission.The data collected at both baseline and impact assessment will be useful to guide global policy on monitoring and evaluation of LF programs that implement IDA-MDA.Indeed, since this study was conducted, interim guidance for IDA-MDA impact surveys (IIS) has come out recommending the testing of adults aged 20 years and above for CFA in 30 randomly selected clusters, with follow-up night time blood samples collected from the CFA positive individuals and examined for microfilaremia.While this IIS approach leverages random selection of clusters (with probability proportionate to estimated size sampling), it is preceded by an epidemiological monitoring survey conducted in two purposively selected high-risk sites.Further work is needed to understand the potential roles for MBG, xenomonitoring and serology to support LF surveillance; this and any follow-on studies in Kenya are well-suited to contribute to this important effort.

Table 4 .Fig 1 .Fig 2 .
Fig 1.A map showing filarial antigenemia rates by FTS test at baseline in 2018 and impact assessment in 2021 (after 2 rounds of IDA-MDA) among study clusters in Jomvu and Lamu evaluation units.The inset map of Kenya shows the location of the two study areas.The map was created using ArcGIS Desktop version 10.2.2 software (Environmental Systems Research Institute Inc., Redlands, CA, USA).The base layer of the map was obtained from Environmental Systems Research, Inc. (ESRI) (https://www.esri.com/en-us/arcgis/products/arcgis-online/resources).https://doi.org/10.1371/journal.pntd.0011942.g001 Baseline prevalenceÀ Endline prevalenceAll statistical analyses were carried out using STATA version 16.1 (STATA Corporation, College Station, TX, USA).Graphs were developed using the ggplot package implemented in R software.Village locations were mapped using ArcGIS Desktop version 10.2.2 software (Environmental Systems Research Institute Inc., Redlands, CA, USA).

Table 2 . Baseline and IDA-MDA impact assessment survey characteristics in each evaluation unit (EU).
*Adult population consisted of individuals aged 10 years and above (baseline) and persons aged 18 years and above (impact assessment); the child population consisted of 5-9 years old children both during baseline survey and impact assessment.https://doi.org/10.1371/journal.pntd.0011942.t002